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Epigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment.

Mélanie A Eckersley-MaslinAled ParryMarloes BlotenburgChristel KruegerYoko ItoValar Nila Roamio FranklinMasashi NaritaClive S D'SantosJuan I Garaycoechea
Published in: Nature structural & molecular biology (2020)
How the epigenetic landscape is established in development is still being elucidated. Here, we uncover developmental pluripotency associated 2 and 4 (DPPA2/4) as epigenetic priming factors that establish a permissive epigenetic landscape at a subset of developmentally important bivalent promoters characterized by low expression and poised RNA-polymerase. Differentiation assays reveal that Dppa2/4 double knockout mouse embryonic stem cells fail to exit pluripotency and differentiate efficiently. DPPA2/4 bind both H3K4me3-marked and bivalent gene promoters and associate with COMPASS- and Polycomb-bound chromatin. Comparing knockout and inducible knockdown systems, we find that acute depletion of DPPA2/4 results in rapid loss of H3K4me3 from key bivalent genes, while H3K27me3 is initially more stable but lost following extended culture. Consequently, upon DPPA2/4 depletion, these promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel epigenetic priming mechanism at developmental promoters, poising them for future lineage-specific activation.
Keyphrases
  • dna methylation
  • genome wide
  • embryonic stem cells
  • gene expression
  • single cell
  • cell fate
  • copy number
  • poor prognosis
  • high throughput
  • dna damage
  • transcription factor
  • hepatitis b virus